This invention relates to a bisoprolol multiparticulate formulation for oral administration and, in particular, to a bisoprolol formulation for chronotherapeutic delivery which can be used for night-time dosing so as to minimise the likelihood of acute cardiovascular occurrences in the well-documented high risk period in the morning.
Bisoprolol (1-[4-[[2-(1-methylethoxy)ethoxy]-methyl]phenoxy]-3-[1-methylethyl)amino]-2-propanol) is a xcex2-adrenoreceptor blocking drug which was first synthesised and developed by E. Merck (U.S. Pat. No. 4,258,062) and was first introduced into the German market in 1986. It is highly xcex2-adrenoreceptor selective and is cleared in equal parts unchanged by the kidneys, and by biotransformation in the liver. Bisoprolol is indicated for therapeutic use in the following areas; the control of arterial hypertension, the management of ischaemic heart disease, the control of some forms of cardiac arrhythmias and in the adjunctive management of hyperthyroidism.
Following oral administration, 90% of bisoprolol is absorbed from the gastrointestinal tract. Peak plasma concentrations are achieved after three hours, (40 ng/ml after a 10 mg dose), and appear not to be affected by concomitant food intake or fasting. The systemic bioavailability of bisoprolol is 90% and hence pre-systemic metabolism is below 10%. The mean plasma half life of 10-12 hours is long compared to other xcex2-blockers. About 50% is excreted unchanged in the urine, the other 50% is biotransformed in the liver with subsequent elimination of pharmacologically inactive metabolites via the kidneys. The pharmacokinetic properties of bisoprolol are not dependent on age or dose in the range 2.5-100 mg.
Generally xcex2-blockers are well tolerated drugs. As far as symptomatic adverse effects are concerned, bisoprolol shows a similar pattern to other xcex2-blockers. Dizziness, headache and tiredness are the most frequent adverse effects spontaneously mentioned by patients treated with bisoprolol. Occasionally cold extremities, sleep disturbances, gastrointestinal upset, weakness of the legs, impotence and sweating have been reported. These effects disappeared in the course of the treatment or when dosage was reduced.
It has been well documented that there is a high risk period in the morning in which there is an increase in acute cardiovascular occurences such as sudden death, myocardial infarction and acute cerebrovascular events. Bisoprolol formulations which are currently dosed in the morning, (with an elimination half life of 10-12 hours), provide therapeutic plasma concentrations over the entire day. However, in order to ensure therapeutic plasma concentrations of bisoprolol on wakening, an evening dosed formulation might be more appropriate.
The aim of the present invention was to achieve such a bisoprolol formulation suitable for night-time dosing with the attendant advantages.
The invention provides a multiparticulate bisoprolol formulation for once-daily oral administration, each particle comprising a core of bisoprolol or a pharmaceutically acceptable salt thereof surrounded by a polymeric coating, said polymeric coating being effective to achieve an initial lag of bisoprolol release in vivo of at least 4-6 hours following administration and thereafter maintaining therapeutic concentrations of bisoprolol for the remainder of the twenty-four hour period.
By lag in bisoprolol release herein is meant zero or minimal release.
The formulation according to the invention enables one to achieve a sufficient delay in release while the patient is asleep, immediate drug release just prior to or following wakening and additionally maintenance of therapeutic concentrations over the dosing interval.
Preferably, the polymeric coating is effective to prevent quantifiable bisoprolol plasma concentrations, such as concentrations of bisoprolol greater than 1 ng/ml, in vivo for a period of at least 3-6 hours.
The initial lag period can be followed by a rapid rise in bisoprolol concentration.
Preferably, the formulation according to the invention contains a pharmaceutically acceptable salt of bisoprolol such as acid addition salts produced by reacting bisoprolol with a suitable acid to produce a pharmaceutically acceptable salt. Suitable salts include those of inorganic acids such as sulphuric acid, nitric acid, hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, and phosphoric acid, such as orthophosphoric acid, and organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic or sulphonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenyl-propionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulphonic acid, ethanedisulphonic acid, 2-hydroxyethanesulphonic acid, benzenesulphonic acid, p-tolunesulphonic acid and naphthalene-mono- and di-sulphonic acids.
A preferred salt is bisoprolol fumarate. A particularly preferred salt is bisoprolol hemifumarate, also referred to as bisoprolol fumarate 2:1.
While bisoprolol is typically available in racemic form, formulations according to the invention can contain racemic bisoprolol or enantiomers of bisoprolol either as enantiomeric mixtures or as a substantially purified enantiomer. Thus, as used herein, bisoprolol refers to both racemic and enantiomeric forms of bisoprolol.
Preferably, the bisoprolol active ingredient will comprise 0.5-20%, more especially to 0.5-8%, and most especially 0.5-4% of the total weight of the multiparticulates.
A provisional in vitro dissolution profile for a bisoprolol multiparticulate formulation suitable for night-time dosing was considered to be:
In practice little correlation was found between in vitro release and in vivo plasma concentration required to achieve the desired therapeutic effects. Although not wishing to be bound by any theoretical explanation of the invention, the delayed release obtained in vivo following night-time dosing is considered to be affected by decreased gastric and possibly intestinal motility during sleep.
A representative in vitro dissolution profile for pH independent multiparticulates is an in vitro dissolution which when measured in a U.S. Pharmacopoeia 2 Apparatus (Paddles) in phosphate buffer at pH 6.8 at 37xc2x0 C. and 50 rpm substantially corresponds to the following:
(a) from 0% to 10% of the total bisoprolol is released after 2 hours of measurement in said apparatus;
(b) from 0% to 50% of the total bisoprolol is released after 4 hours of measurement in said apparatus; and
(c) greater than 50% of the total bisoprolol is released after 10 hours of measurement in said apparatus.
A representative in vitro dissolution profile for pH dependent multiparticulates is an in vitro dissolution which when measured in a U.S. Pharmacopoeia 1 Apparatus (Baskets) at 37xc2x0 C. and 50 rpm in 0.01 N HCl for the first 2 hours followed by transfer to phosphate buffer at pH 6.8 for the remainder of the measuring period substantially corresponds to the following:
(a) from 0% to 10% of the total bisoprolol is released after 2 hours of measurement in said apparatus;
(b) less than 50% of the total bisoprolol is released after 4 hours of measurement in said apparatus; and
(c) greater than 20% of the total bisoprolol is released after 10 hours of measurement in said apparatus.
A sealant or barrier layer can be applied to the core prior to the application of the polymeric coating.
The sealant or barrier layer does not modify the release of bisoprolol significantly. Suitable sealants or barriers are permeable or soluble agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose and xanthan gum. Hydroxypropyl methylcellulose is preferred.
Other agents can be added to improve the processability of the sealant or barrier layer. Such agents include talc, colloidal silica, polyvinyl alcohol, titanium dioxide, micronised silica, fumed silica, glycerol monostearate, magnesium trisilicate or magnesium stearate or a mixture thereof.
The sealant or barrier layer can be applied from solution (preferably aqueous) or suspension using a fluidised bed coater (preferably Wurster coating), or in a pan coating system.
Such sealants or barrier coatings are commercially available such as those sold under the Trade Marks OPADRY WHITE Y-1-7000 and OPADRY OY/B/28920 WHITE each of which is available from Colorcon Limited, England.
Preferably, the bisoprolol active ingredient is applied to a non-pareil seed having an average diameter in the range of 0.4-1.1 mm, more especially 0.85-1.00 mm.
The cores can be formed by coating the active ingredient onto inert cores (e.g. non-pareil seeds) to form instant release multiparticulates. The active ingredient can be applied with or without additional excipients onto the inert cores. The active ingredient can be sprayed from solution (preferably aqueous) or suspension using a fluidised bed coater (preferably Wurster coating), or in a pan coating system. Alternatively, the active ingredient can be applied as a powder onto the inert cores using a binder to bind the active ingredient onto the cores. Cores can also be formed by extrusion of the core with suitable plasticisers as described below and any other processing aids as necessary.
A wide range of polymers can be used in the polymer coating. These polymers include enteric polymer coating materials, such as cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, Eudragit(copyright) poly acrylic acid and poly acrylate and methacrylate coatings such as Eudragit(copyright) S or Eudragit(copyright) L, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch and cellulose based cross-linked polymers in generalxe2x80x94the degree of cross-linking should be low so as to facilitate adsorption of water and expansion of the polymer matrix, hydoxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, cellulose acetate cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose triacetate, aminoacryl-methacrylate copolymer (Eudragit(copyright) RS-PM, Rohm and Haas), pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose, (swellable hydrophilic polymers) poly (hydroxyalkyl methacrylate) (m. wt. xcx9c5 k-5,000 k), polyvinylpyrrolidone (m. wt. xcx9c10 k-360 k), anionic and cationic hydrogels, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (m. wt. xcx9c30 k-300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox(copyright) polyethylene oxides (m. wt. xcx9c100 k-5,000 k), AquaKeep(copyright) acrylate polymers, diesters of polyglucan, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate (e.g. Explotab(copyright); Edward Mandell C. Ltd.); hydrophilic polymers such as polysaccharides, methyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, poly(ethylene terphthalate), poly(vinyl isobutyl ether), polyurethane, polyethylene oxides (e.g. Polyox(copyright), Union Carbide), methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, ethylcellulose, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, ammonio methacrylate copolymers such as Eudragit(copyright) RL or Eudragit(copyright) RS (e.g. Eudragit(copyright), Rohm and Haas), other acrylic acid derivatives, sorbitan esters, polydimethyl siloxane, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, gums: arabic, karaya, locust bean, tragacanth, carrageenans, guar, xanthan, scleroglucan and mixtures and blends thereof.
However, preferably, the polymeric coating contains a major proportion of a pharmaceutically acceptable film-forming polymer which forms an insoluble film of low permeability.
In one embodiment, the polymeric coating contains a minor proportion of a pharmaceutically acceptable film-forming polymer which forms an insoluble film of high permeability.
Further, preferably, the or each polymer is a methacrylic acid co-polymer.
Alternatively, the or each polymer is an ammonio methacrylate co-polymer.
However, a mixture of methacrylic acid co-polymers and ammonio methacrylate co-polymers can be used.
Methacrylic acid co-polymers which include polymers sold under the Trade Marks Eudragit S and Eudragit L by Rohm and Haas are particularly suitable for use in the formulations according to the invention.
These polymers are gastroresistant and enterosoluble polymers. The polymer films are insoluble in pure water and diluted acids. They dissolve at higher pHs, the value of which depends on their content of carboxylic acid. Eudragit S and Eudragit L can be used as single components in the polymer coating
Alternatively, the polymers Eudragit S and Eudragit L can be combined in the one coating film in any ratio. By using a combination of the polymers theoretically results in coating films which are soluble at a pH between the pHs at which Eudragit L and Eudragit S are soluble.
Ammonio methacrylate co-polymers which include polymers sold under the Trade Marks Eudragit RS and Eudragit RL by Rohm and Haas are also particularly suitable for use in the formulations according to the invention. These polymers are insoluble in pure water, dilute acids, buffer solutions or digestive fluids over the entire physiological pH range. The films swell in water (and digestive fluids independently of pH). In the swollen state they are then permeable to water and dissolved actives. The permeability of the films depends on the ratio of ethylacrylate (EA), methyl methacrylate (MMA) and trimethylammonioethyl methacrylate chloride (TAMCl) groups in the polymer. Those polymers having EA:MMA:TAMCl ratios of 1:2:0.2 (Eudragit RL) are more permeable than those with ratios of 1:2:0.1 (Eudragit RS). Films of Eudragit RL are described as being xe2x80x9cinsoluble films of high permeabilityxe2x80x9d and films of Eudragit RS are described as being xe2x80x9cinsoluble films of low permeabilityxe2x80x9d.
Suitably the ammonio methacrylate co-polymers are combined in the ratio of Eudragit RS:Eudragit RL (90:10). However, the two polymers can be combined in a range of ratios. To create the required lag period, the polymers should preferably be combined in ratios in the range of 100:0 to 80:20 Eudragit RS:Eudragit RL, more especially 100:0 to 90:10 Eudragit RS:Eudragit RL, i.e., the major portion of the film coat would be the less permeable polymer Eudragit RS.
The ammonio methacrylate co-polymers can be combined with the methacrylic acid co-polymers within the one film coat in order to achieve a lag. Ratios of ammonio methacrylate co-polymer (particularly Eudragit RS) to methacrylic acid co-polymer in the range of 99:1 to 20:80 can be used to create a lag in release.
The two types of polymers can also be combined in any ratio in separate coats on the cores as hereafter exemplified.
In addition to the Eudragit polymers described above, a number of other such polymers can be used to create a lag in release. These include methacrylate ester co-polymers (e.g. Eudragit NE 30D).
Further information on the Eudragit polymers is to be found in Chemistry and Application Properties of Polymethacrylate Coating Systemsxe2x80x9d from xe2x80x9cAqueous Polymeric Coatings for Pharmaceutical Dosage Formsxe2x80x9d edited by James McGinity (Marcel Dekker Inc., New York) pg 109-114).
Preferably, the polymeric coating includes one or more soluble excipients so as to increase the permeability of the coating.
Suitably, the or each soluble excipient is selected from a soluble polymer, a surfactant, an alkali metal salt, an organic acid, a sugar and a sugar alcohol.
Such soluble excipients include polyvinyl pyrrolidone, polyethylene glycol, sodium chloride, surfactants such as sodium lauryl sulphate and polysorbates, organic acids such as acetic acid, adipic acid, citric acid, fumaric acid, glutaric acid, malic acid, succinic acid, and tartaric acid and sugars such as dextrose, fructose, glucose, lactose and sucrose, and sugar alcohols such as lactitol, maltitol, mannitol, sorbitol and xylitol, xanthan gum, dextrins, poloxamers and maltodextrins,
Polyvinyl pyrrolidone, mannitol and polyethylene glycol are the preferred soluble excipients.
Preferably, the soluble excipient is used in an amount of from 1% to 10% by weight, based on the total dry weight of the polymer.
The polymeric coating can also include one or more auxiliary agents selected from a filler, a plasticiser and an anti-foaming agent.
Representative fillers include talc, fumed silica, glyceryl monostearate, magnesium stearate, calcium stearate, kaolin, colloidal silica, gypsum, micronised silica and magnesium trisilicate.
Talc is the preferred filler.
The quantity of filler used is from about 2% to about 300% by weight, preferably 20 to 100%, based on the total dry weight of the polymer.
The coatings can also include a material that improves the processing of the polymers. Such materials are generally referred to as xe2x80x9cplasticisersxe2x80x9d and include, for example, adipates, azelates, benzoates, citrates, isoebucates, phthalates, sebacates, stearates and glycols.
Representative plasticisers include acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; ethylene glycol, propylene glycol; triacetin citrate; triacetin; tripropinoin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, glyceryl monocaprylate and glyceryl monocaprate.
Dibutyl sebacate is the preferred plasticiser.
The amount of plasticiser to be used in the coating is preferably from about 10% to 50%, most preferably about 20%, based on the weight of the dry polymer.
An example of an anti-foaming agent is Simethicone. The amount of anti-foaming agent to be used in the coating is preferably from 0% to 0.5% of the final formulation.
The amount of coating to be used in forming the multiparticulates will be determined by the desired delivery properties, including the amount of drug to be delivered, the time delay desired, and the size of the multiparticulates. The coating polymers will be coated to 10 to 100% weight gain on the cores, preferably 25-70% polymer weight gain. The coating on the multiparticulates providing the delay, including all solid components of the coating such as co-polymer, filler, plasticiser and optional additives and processing aids, is from about 11% to 450% weight gain on the cores, preferably 30% to 160% weight gain. The polymer layer can be coated by any known method, including spray application. Spraying can be carried out using a fluidised bed coater (preferably Wurster coating), or in a pan coating system.
The coated cores are dried or cured after application of the polymer layer(s). xe2x80x9cCuringxe2x80x9d means that the multiparticulates are held at a controlled temperature for a time sufficient to provide stable release rates. Curing can be performed for example in an oven or in a fluid bed drier. Curing can be carried out at any temperature above room temperature.
A sealant or barrier layer can be applied to the polymeric coating.
The sealant or barrier layer, when such is present, can be formed of any of the materials hereinabove specified for the sealant or barrier layer applied to the core.
The sealant or barrier layer may be applied to the polymeric coating to prevent agglomeration of the multiparticulates.
The invention also provides an oral dosage form containing a multiparticulate bisoprolol formulation as hereinabove defined, which is in the form of caplets, capsules, particles for suspension prior to dosing, sachets or tablets.
When the dosage form is in the form of tablets, the tablets are preferably selected from disintegrating tablets, fast dissolving tablets, effervescent tablets, fast melt tablets and mini-tablets.
The dosage form can be of any shape suitable for oral administration of a drug, such as spheroidal, cube-shaped oval or ellipsoidal.
The dosage form will suitably contain from 1-30 mg, preferably 1.25-10 mg, of active ingredient. The dosage forms will be prepared from the multiparticulates in a manner known per se, including additional excipients, where required.